A dramatic shift has occurred over the last decade in the route of cocaine administration by drug abusers in the United States. The favored route has changed from intranasal and intravenous use to administration of cocaine ("crack") by the smoking route. The reasons for this shift are not well understood, but may include social and environmental factors such as the ease and convenience of the smoking route, avoidance of needle-transmitted disease, and possible pharmacologic differences produced by the different routes of administration. This study examined the influences exerted by changes in the route of administration on pharmacokinetic parameters and drug-induced behavioral and physiologic effects of cocaine. Six male subjects who provided informed consent and had a recent history of cocaine use by the intravenous and smoked routes participated in a blind, double-dummy, cross-over study conducted on a clinical research ward. On different occasions subjects received single doses of cocaine by the intravenous (25 mg, cocaine HCl), intranasal (32 mg, cocaine HCl) and smoked (42 mg, cocaine base) routes. Physiologic and behavioral measures were collected prior to and periodically after drug administration. Concurrent blood samples were collected and analyzed by gas chromatography/mass spectrometry for cocaine and metabolites. Plasma concentrations of cocaine and benzoylecgonine were fitted to pharmacokinetic models by non-linear regression analysis. Behavioral measures of "good" drug effects and "liking" were higher by the smoked route than the intravenous route, but physiologic changes were approximately equal at equivalent plasma concentrations of cocaine. Intranasal cocaine administration was characterized by lower cocaine plasma concentrations and a slower onset of pharmacologic effects that were generally of lesser magnitude than those observed by other routes of administration. Overall, this study demonstrated that cocaine administration by the smoked route produced substantially higher behavioral responses than an equivalent dose of cocaine administered by the intravenous route. This finding suggests that smoked cocaine ("crack") has a higher abuse liability and greater dependence-producing properties than equivalent doses of cocaine administered by the intravenous or intranasal route.